For rapidly mutating viruses such as influenza and SARS‑CoV‑2, prior immune priming can shape subsequent antibody responses. When individuals with immunity to an original strain encounter antigenically drifted variants, the immune system often preferentially recalls antibodies directed at the priming strain rather than generating entirely new responses. This phenomenon is known as immune imprinting or original antigenic sin. The article reports analysis of human antibody responses after sequential exposures to SARS‑CoV‑2 variants in people initially primed with ancestral (WA1) spike antigens.
Initial vaccines were developed from ancestral WA1 spike sequences and provided high early efficacy, preventing substantial morbidity and mortality. Subsequent antigenic drift and occasional larger evolutionary shifts produced spike mutations that reduced recognition by vaccine‑ and infection‑elicited antibodies. To address waning neutralization against circulating Omicron subvariants, multiple booster updates were issued, including a WA1‑BA.5 bivalent in 2022 and further strain‑matched boosters (XBB.1.5 in 2023, KP.2 in 2024 and LP.8.1 in 2025). These sequential updates mean that many individuals have experienced repeated exposures to progressively divergent antigens on a background of ancestral immunity.
To understand the composition and function of antibodies elicited by variant exposures, the authors isolated and characterized hundreds of neutralizing monoclonal antibodies from ancestrally imprinted humans after sequential variant encounters. Analysis separated antibodies into two major categories: ancestral cross‑reactive (recall) antibodies, which recognize epitopes conserved with the priming strain, and de novo variant type‑specific antibodies, which arise after exposure to the variant and target variant‑specific features.
The de novo antibodies exhibited several distinguishing features compared with recall antibodies. They used different V(D)J gene segments and were generally closer to germline sequence, indicating fewer somatic mutations. Functionally, de novo antibodies targeted distinct receptor binding domain (RBD) epitopes compared with ancestral cross‑reactive antibodies and showed potent neutralizing activity against subsequent variants. These properties suggest that de novo responses can provide high‑potency, type‑specific neutralization that complements the broader but imprint‑biased recall repertoire.
Despite detection of potent de novo type‑specific antibodies, the authors found that neutralizing responses elicited by the 2024–2025 updated booster were still predominantly ancestral cross‑reactive. In other words, antibody recall to epitopes shared with the original WA1 strain remained the dominant component of the measured neutralizing response even after administration of updated variant‑focused boosters. This finding highlights the enduring influence of primary imprinting on the composition of the circulating neutralizing antibody pool.
The study delineates complementary roles for recall and de novo antibody subsets in the immune response to SARS‑CoV‑2 variants. Recall antibodies provide broad cross‑reactivity based on the priming antigen, while de novo antibodies supply potent, variant‑specific neutralization directed at distinct RBD epitopes. The observation that updated boosters increased both subsets underlines the benefit of variant‑matched vaccine updates in augmenting the overall neutralizing response.
At a population level, the persistent dominance of ancestral cross‑reactive responses after boosting underscores the complex immunological landscape produced by sequential exposures. The findings align SARS‑CoV‑2 immunology with patterns long studied in influenza and reinforce the rationale for periodic vaccine updates to address antigenic drift and restore neutralization against circulating variants.
This rewritten summary is based only on the information provided in the article abstract and early Main text. Specific experimental methods, quantitative results, cohort details and additional data reported in the full manuscript were not reproduced here because they were not included in the provided text.